In recent years, a number of academic research groups have directed their interests toward oligomers and polymers comprised of β-amino acid residues. These compounds are collectively referred to herein as β-peptides or β-polypeptides. β-polypeptides differ from naturally occurring α-polypeptides by the presence of an additional carbon atom (the β-carbon) situated between the amino terminus and the carboxy terminus in the backbone of the polypeptide.
Over the past decade, the synthesis, properties and functions of β-peptides have been the subject of extensive study by a number of research groups. See, for example, Cheng, Gellman & DeGrado (2001) Chem. Rev. 101:3219-3232. The interest in β-polypeptides is due, in part, to the discovery that these compounds can adopt stable secondary structures (“foldamers”) that mimic natural peptides. See Gellman et al. (1998) Acc. Chem. Res. 31:173. Certain β-polypeptides have been shown to exhibit important biological activity, including cholesterol absorption inhibition and antimicrobial activity. Oligo-β-peptides generally must be prepared via solid-phase synthesis, a relatively costly and labor-intensive technique that restricts the scope and scale of possible uses for β-polypeptides, despite their favorable activities.
β-peptides are entirely non-natural. Thus, β-peptides are resistant to enzymatic degradation, in contrast to α-peptides. In short, β-peptides mimic α-peptides in many key aspects (most notably the adoption of stable secondary conformation) but because they are non-natural, β-peptides are not as prone to breakdown in biological milieus as are naturally occurring α-peptides.
Large-scale synthesis of β-peptides is difficult because the standard preparative methods involve step-wise, residue-by-residue synthesis. Thus, much of the scientific literature relating to β-polypeptides approaches the subject as a direct spin-off from α-polypeptide chemistry: The β-polypeptides are synthesized by solution-phase or solid-phase chemistries, residue-by-residue. In the U.S. patent literature, see, for example, U.S. Pat. Nos. 6,060,585; 6,613,876; and 6,683,154, all to Gellman et al. See also U.S. Pat. No. 6,617, 425, to Seebach. In the scientific literature, see, for example, Gellman et al. (2004) Organic Letters 6(24):4411-4; and Gellman et al. (1996) J. Am. Chem. Soc. 118:13071. See also Seebach et al. (1996) Helv. Chim. Acta. 79:913-941; and Seebach et al. (1996) Helv. Chim. Acta. 79:2043-2066. Antibacterial compositions containing β-peptides are described in Hamuro et al. (1999) J. Am. Chem. Soc. 121:12200-12201.
Polymerization routes to β-peptides have been problematic mainly due to the poor solubility of the resulting β-polypeptide chain, which limits the ability of the conventional routes to yield large β-polypeptides having a diverse number of derivatives. One route that has been investigated by a number of groups is a ring-opening polymerization of β-lactams. See Graf et al. (1962) Angew. Chem. Int. Ed. 1:481; Sebenda et al. (1976) J Polym Sci: Pol. Chem. 14:2357; Lopez-Carrasquero et al. (1994) Polymer 35:4502; Garcia-Alvarez et al. (1994) Syn. Commun. 24:745; Hashimoto (2000) Prog. Polym. Sci. 25:1411; and Cheng et al. (2001) J. Am. Chem. Soc. 123:9457. Each of these routes, however, suffers from serious shortcomings related to low product solubility and difficulty in characterizing the resulting products. Despite their apparent convenience, the polymerization techniques described in these references require high-purity reagents and solvents. Reaction conditions must be carefully controlled and maintained or the polymerization falters. The conventional reactions as taught in the cited references simply are intolerant to impurities. The solvent systems that can be employed are also limited. Sebenda et al. frankly stated that “It is known that polymers of β-lactams are only soluble in strongly polar solvents which interfere with anionic polymerization.” In other words, the solvents required to keep the growing polymer chain in solution are solvents that are not conducive to anionic polymerization.
The patent literature likewise contains a number of issued U.S. patents directed to various aspects of lactam polymerization. See, for example, Deming et al., U.S. Pat. No. 6,818,732. See also U.S. Pat. Nos. 6,881,819; 6,835,774; 6,013,758; 5,864,007, 5,756,647, 4,695,611; and 4,677,189.
Thus, there remains a long-felt and unmet need for a synthetic route to make large β-peptides (e.g., about 1 kDa or larger) that can be controlled to yield homopolymers, random co-polymers, block copolymers, etc. of a desired molecular weight range and distribution.